Acta Neuropsychiatrica 2011: 23: 3–11All rights reservedDOI: 10.1111/j.1601-5215.2010.00508.x

© 2011 John Wiley & Sons A/S

ACTA NEUROPSYCHIATRICA

Review article

Tryptophan and depression: can diet alonebe the answer?

Soh NL, Walter G. Tryptophan and depression: can diet alone be theanswer?

Objective: To compare the scientific content of recent general mediaarticles on tryptophan, diet and depression, with recent empirical researchinto dietary manipulation of tryptophan published in the scientificliterature.Method: A review of the recent empirical research into the role oftryptophan in depression, focusing on dietary methods to influencetryptophan levels. In parallel, a review of recent articles in the generalEnglish language media regarding tryptophan and mood.Results: Empirical evidence for improving mood through dietarymanipulation of tryptophan is lacking, and it is difficult to change plasmatryptophan levels through diet alone. Tryptophan supplementation anddepletion studies suggest that altering tryptophan levels may only benefitcertain groups of patients who have a personal or family history ofdepression. Scientific studies also focus on elucidating mechanisms indepression, rather than treating depression by changing tryptophan levels.However, general media articles often recommend diets and foods toincrease blood tryptophan levels and raise brain serotonin levels. Suchrecommendations are not supported by scientific studies.Conclusion: It is very difficult to alter blood tryptophan levels throughdietary methods alone, outside of a laboratory or research setting. Only asmall number of lay articles provide sound advice, with general mediareports on tryptophan often being hyperbolic and misleading. A clinicianshould be aware of the type of (mis)information a patient may haveaccessed and have the scientific knowledge to explain the impracticalitiesof influencing tryptophan levels through diet alone.

Nerissa L. Soh1,Garry Walter1,2,3

1Child and Adolescent Mental Health Services,Northern Sydney Central Coast Area Health, NorthRyde New South Wales, Australia; 2Child andAdolescent Psychiatry, University of Sydney, NewSouth Wales, Australia; and 3Department ofPsychiatry, Dalhousie University, Halifax, Canada

Keywords: depression; diet; media;serotonin; tryptophan

Dr Nerissa L. Soh,Child and Adolescent Mental Health Services,Northern Sydney Central Coast Area Health, CoralTree Family Service, PO Box 142, North Ryde NSW1670, Australia.Tel: +61 2 8877 5371;Fax: +61 2 9887 2941;E-mail: nsoh@nsccahs.health.nsw.gov.au

Introduction

A patient with symptoms of depression is assessedby a psychiatrist and, when treatment is discussed,mentions reading about tryptophan being of potentialbenefit ‘because it turns into serotonin in the brain’.The patient wants to try a tryptophan-rich diet andasks for the psychiatrist’s overall opinion about thematter and advice on how to achieve such a diet.

What advice should the psychiatrist give? Thisreview focuses on dietary methods to influence tryp-tophan levels, the clinical applications this may haveand the empirical research supporting the role of tryp-tophan in depression, particularly studies publishedin the last 10 years and also earlier relevant studies.

The article also examines the information providedby the general English language media regardingtryptophan and mood over the past few years, butdoes not focus on the role of tryptophan in sleepdisorders, behaviour, anxiety, attention or cognition.

Tryptophan’s role in mood

Tryptophan’s potential as a treatment for depressionhas been given much attention by the general media.A search using ‘tryptophan’ and ‘mood’ as keywordsin Factiva, a search engine for general mediapublications, particularly newspapers and magazines,yielded 1461 citations from 1986 to February 2010.The Factiva search was for English language articles

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and these were published in newspapers from a widerange of countries and regions, including the UnitedKingdom, United States, Canada, the Philippines,India, Pakistan, Middle-East, Singapore, Australiaand New Zealand.

Tryptophan is an essential amino acid; a sub-unit in protein molecules and a precursor to sero-tonin. It cannot be synthesised by the body andmust be obtained only through diet; the averagedaily requirement for adult humans being 4 mg/kgbody weight (1). A Cochrane Review of the efficacyof oral tryptophan and 5-hydroxytryptophan (5-HT)supplementation as treatments for depression con-cluded that there was insufficient evidence that eitheris more effective than placebo in unipolar depres-sion (2). However, because of the strictness of theinclusion criteria, there were only two studies, pub-lished in 1972 and 1982, in this meta-analysis. Allthe studies reviewed, including those rejected, werequite old and were published from 1964 to 1999,despite a search update in 2004.

Altering dietary intakes of protein and carbohy-drate can theoretically modify mood by manipulat-ing tryptophan uptake by the brain. The Wurtmanhypothesis states that a carbohydrate-rich meal stim-ulates insulin secretion and causes most of the aminoacids in the bloodstream, other than tryptophan, tobe taken up by the peripheral tissues (3–5). Theresulting higher ratio of tryptophan to other largeneutral amino acids (LNAAs) (valine, isoleucine,leucine, tyrosine, phenylalanine, methionine and his-tidine) (6) leads to a greater transport of tryptophanto the brain.

Changing tryptophan levels by diet

There are very few published studies in humanswhich manipulate plasma tryptophan levels bydietary means alone. Merens et al.’s 2007 reviewof empirical studies that manipulated tryptophan lev-els through supplementation or depletion techniquesdid not report any studies that used solely dietarymethods (7). The study by Markus et al. (8) is oneof the few to use dietary techniques. Plasma tryp-tophan:LNAA ratios rose significantly on admin-istering high-carbohydrate-low-protein diets (pro-tein content 3.9–5% of caloric intake), by anaverage of 42% above the ratio when on high-protein-low-carbohydrate diets. Inclination to stresswas measured through the Inadequacy Scale ofthe Dutch Personality Inventory, which assessesneuroticism, and in individuals highly prone tostress, high-protein-low-carbohydrate diets increaseddepression when stress was induced. However, inindividuals less prone to stress, both high-protein-low-carbohydrate and low-protein-high-carbohydrate

diets led to increased severity of depression. It is notknown if the test diets influenced the fasting aminoacid profiles as baseline plasma amino acid ratioswere not measured, and also the test meals wereadministered only on the test day rather than as long-term diets. Wurtman et al.’s more recent study (9)showed that the protein and carbohydrate content of ameal can significantly alter plasma tryptophan:LNAAratios in healthy adults. In this 2003 randomisedcrossover trial, a high-carbohydrate breakfast (69.9 gcarbohydrate, 5.2 g protein) initially lowered tryp-tophan:LNAA ratios below baseline, with the ratiothen increasing over the 3 h of the test, albeit notsignificantly. In contrast, the high-protein breakfast(15.4 g carbohydrate, 46.8 g protein) significantlylowered plasma tryptophan:LNAA ratios from base-line, by 35% at 3 h. Wurtman et al.’s test meals weredesigned to reflect typical breakfasts consumed inthe United States, but the study had a small sample(n = 9) and did not include psychological measures;it is not known if the changes in amino acid pro-file were associated with mood changes. The authorshighlighted that while the combination of variousfoods in a meal would mitigate changes to serotoninsynthesis, snacks may be composed of a single fooditem and if it is very high or low in protein, its impacton brain serotonin would be mostly unmoderated.However, Wurtman et al. also noted that the effectswould be confounded by the composition of priormeals (9). In this vein, the composition of subsequentmeals, snacks or beverages and the time betweenconsumption would also confound the effects of a‘single-item snack’ on serotonin levels. It is question-able how long the changes in brain serotonin wouldbe sustained in daily life outside of the laboratory.

Energy restriction also lowers plasma tryptophan,but its impact on mood is not consistent. Attenburrowet al.’s study of 50 healthy women (10) found lowcalorie diets (1000 kcal/day) followed over 3 weekssignificantly lowered total plasma tryptophan levelsand total plasma tryptophan:branched chain aminoacid ratios, but did not change levels of depression oranxiety symptoms. Further, in a randomised, double-blind placebo-controlled method, the women weresupplemented with 1.8 g tryptophan/day derivedfrom lactalbumin (10). The supplementation did notcircumvent the fall in plasma tryptophan induced bythe weight-loss diet. Attenburrow’s group hypothe-sised that food restriction may upregulate tryptophanmetabolism for which the tryptophan supplementscould not compensate. In contrast, a much older studyby Schweiger et al. (11) into weight-loss diets foundthat plasma tryptophan:LNAA ratios correlated withoverall mood. However, unlike Attenburrow’s studywhere the diet had a fixed macronutrient composi-tion, participants in Schweiger’s study were advised

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only on maintaining a ‘mixed’ or a ‘vegetarian’ dietand so the proportions of protein and carbohydrateintake were not controlled.

Changing tryptophan levels by supplementationand depletion methods

Most empirical studies use supplementation, intra-venous infusions or tryptophan depletion techniquesto alter tryptophan and serotonin levels. Supple-mentation methods include high-tryptophan proteindietary supplements, such as α-lactalbumin, andamino acid supplements. Acute tryptophan depletionis effected through administering amino acid mix-tures without tryptophan, which stimulates proteinsynthesis by the liver and subsequently lowers thebody’s endogenous pool of plasma tryptophan (12);it is a popular research technique for modifyingplasma tryptophan levels.

As tryptophan is a limiting amino acid in mostfood proteins (3), there are few foods that canbe used as a source of tryptophan. One ‘food’that has been used as a supplement in studiesis α-lactalbumin, a tryptophan-rich whey protein.To investigate the cognitive and mood effects ofα-lactalbumin, Booij et al. (13) supplemented low-protein-high-carbohydrate diets with α-lactalbuminin individuals recovered from depression and incontrols. Although the plasma tryptophan:LNAAratio was 71.5% higher in those supplemented withα-lactalbumin compared with the casein placeboand was 77.5% higher than baseline, there wasno significant improvement in mood from base-line or compared with the placebo group. Firk andMarkus (14) found that individuals supplementedwith α-lactalbumin had improved mood but this didnot occur with casein supplementation; however,this study did not measure plasma amino acid pro-files. Merens et al. (15) significantly increased theplasma tryptophan:LNAA ratio in individuals witha history of depression and in healthy participantsby 21% from baseline, also using α-lactalbumin.α-Lactalbumin did not elicit a significant differencein mood compared with those taking casein sup-plements as a placebo, despite casein promoting asignificant decrease in tryptophan:LNAA, and therewere minimal differences when the participants wereplaced under stress. It is possible that a larger loadof α-lactalbumin is required to influence mood (15).

An older study by Beulens et al. (16) raisedplasma tryptophan:LNAA ratios in young healthymen by 16% by supplementing a normal diet withα-lactalbumin. The researchers also found no signif-icant difference in mood between supplement andplacebo groups an hour after consumption. All trialswere randomised, double-blind, placebo-controlled

and crossover, and, like the studies by Markus et al.and Wurtman et al. (8,9), the diets and supplementswere administered only on test days and not as long-term dietary regimes. Thus, the findings can onlyrepresent acute effects. It is not clear whether thehealthy status and/or youth of the participants ren-dered them insensitive to such changes in the tryp-tophan:LNAA ratio or whether a greater elevationof the ratio would be required in order for dif-ferences in mood to be detected. Murphy et al.’splacebo-controlled trial is notable in that it supple-mented healthy participants with 3 g tryptophan/dayfor 14 days (17). This trial of 38 participants foundthat tryptophan induced a positive bias in women’sprocessing of emotional material after 14 days, butnot men’s, indicating women may be more sensi-tive to changes in serotonin level. In a similar vein,Moreno et al.’s study of 59 individuals in remissionfor depressive symptoms found women had signifi-cantly greater depressive responses to acute trypto-phan depletion compared with men (18). However,neither study measured plasma or cerebrospinal fluid(CSF) tryptophan levels, and the background diet wasnot controlled for, which may be particularly perti-nent in Murphy’s lengthier trial.

The form in which tryptophan is administeredalso influences its in vivo effects. Markus et al. (19)investigated the differences in administering trypto-phan as intact α-lactalbumin, a protein hydrolysate,pure tryptophan and as a tryptophan dipeptide.Despite providing the same quantities of tryptophan,mood in healthy individuals improved significantlyonly with the protein hydrolysate and pure trypto-phan supplements but not with the casein controlor other forms of tryptophan. The plasma trypto-phan:LNAA ratio increased significantly from base-line with all four versions of tryptophan (peakincreases being 263% for the peptide, 255% forthe hydrolysate, 191% for pure tryptophan and 67%for α-lactalbumin), although with α-lactalbumin theincrease was significantly lower than the proteinhydrolysate and pure tryptophan (19). The source oftryptophan may have implications when trying toincrease plasma tryptophan through dietary meansalone.

Whether or not an individual has a history ofmood disorders also influences their susceptibility tochanges in tryptophan levels. Meren’s 2007 reviewnoted that in healthy subjects, tryptophan manipula-tion had minimal effect on mood and while mooddid decrease in patients with a past or family historyof depression, the results were inconsistent (7). Evenin older individuals in remission and on medication,acute tryptophan depletion had no significant effecton mood and it was hypothesised that longer remis-sion times may be protective (20). Moreno et al.’s

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prospective study (21) observed that individuals weremore likely to experience a depressive episode whenfollowed up over the course of a year, if they hada depressive response to acute tryptophan deple-tion. Moreno included individuals in remission formajor depression and healthy controls and found nocorrelation between the number of previous majordepression episodes and the occurrence of episodeson follow-up, although it was noted that the samplesize was small (n = 24). The inconsistent impact oftryptophan depletion on the mood of those with ahistory of depression was also highlighted by Booijet al.’s meta-analysis (22), where chronic depression,recurrent depressive episodes, being female, previoustreatment with selective serotonin reuptake inhibitors(SSRIs) and a history of serious suicidal thoughtsor attempts were independent predictors of a moodresponse in patients. In Klaassen et al.’s study ofhealthy individuals with and without a family his-tory of depression, tryptophan depletion significantlylowered plasma tryptophan and tryptophan:LNAAratios after 6 h compared with placebo, which wererestored after 24 h, but there were no differencesat baseline (23). There was no difference in moodat baseline between placebo and tryptophan-depletedgroups, but mood significantly lowered in the latter at6 h only in those with a family history of depression.Klaassen et al.’s study is notable as it also controlledbackground protein intake using low-protein diet forthe 24 h of the study.

As highlighted by Merens et al. (7), there is a lackof studies in participants with current depression.Booij et al. (24) studied acute tryptophan depletionin patients who were depressed and receiving antide-pressant medication. Depletion of tryptophan and sig-nificantly lowering of tryptophan:LNAA ratios wereassociated with improved mood in patients receivingselective serotonin–noradrenaline reuptake inhibitors(SSNRIs) but there was no change in mood in thosereceiving other types of medication. The reason givenfor the improvement was that long-term treatmentwith SSNRIs desensitises and downregulates sero-tonin receptors 5-HT1, 1A and 2, but in patientswho have not been medicated for very long, deple-tion of tryptophan would not yield the usual decreasein serotonin because of the SSNRIs, and thus mayincrease post-synaptive 5-HT receptor activity. How-ever, the sample size was small (n = 14), withthe authors acknowledging the difficulty of recruit-ing depressed participants. Delgado et al.’s 1994study (25), although older, is remarkable for its largesample of currently depressed patients who were noton medication (n = 43). This double-blind, placebo-controlled crossover trial found that acute trypto-phan depletion significantly reduced plasma-free andtotal tryptophan levels by 83%, but there was no

significant change in depressive symptoms. A lagtime was observed, where there were significant andheterogeneous changes in depressive symptom sever-ity the following day, when plasma tryptophan levelshad recovered. Individuals who had responded to pre-vious antidepressant treatments reported improvedmood according to the Hamilton Depression Rat-ing Scale when compared with placebo, while thosewho had not responded to prior antidepressant treat-ments scored worse (increase by 5–9 points) ormuch worse (increase by 10 or more points) in theirdepressive symptomatology (25). It was speculatedthat acute tryptophan depletion and repletion mayhave sensitised some of the patients’ serotonin func-tion, hence their improved mood, while those whoreported worse mood may have impaired serotoninmetabolism and thus were less able to compensatefor tryptophan depletion. The authors suggested thatserotonergic antidepressants may not be efficaciousin improving the mood of patients with impairedserotonin metabolism.

Plasma tryptophan versus brain tryptophan and serotonin

Most human studies measure plasma tryptophan lev-els, and thus do not directly show whether the tech-niques which alter tryptophan levels in the bloodtranslate to changes in the uptake and metabolismof tryptophan by the brain. Roiser et al. (26) investi-gated regional blood flow in the brain following acutetryptophan depletion, but found no significant changein mood either in healthy participants or in patientswith remitted major depressive disorder. There weredifferences in hemodynamic responses between thetwo groups depending on the treatment. However,the results could not confirm if the hemodynamic dif-ferences were mediated by serotonin and tryptophan.Blomstrand et al. (27) inferred tryptophan uptake bythe brain in human subjects through the difference inblood concentration of tryptophan in the radial arterycompared with that of the jugular vein, although thisstudy’s focus was on the impact of carbohydrateintake on amino acid uptake during exercise, ratherthan mood.

Radio-labelled 3-(11)C-amino-4(2-dimethylamino-methylphenylsulfanyl)benzonitrile has been used tostudy the binding potential of the serotonin trans-porter 5-HTT in the brains of healthy humans (28).Binding potential is an index of the expression andaffinity of 5-HTT and this study found that there wasno difference in 5-HTT binding potential betweencontrol and depleted states in any region of thebrain assessed. This was despite significantly low-ering plasma tryptophan by 90% through tryptophandepletion, indicating that the degree of transport ofserotonin in the brain was not altered. Mood was not

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assessed but the absence of change in binding poten-tial is congruent with the frequent observation thathealthy individuals are protected against the mood-lowering effects of tryptophan depletion (28). Itwould be interesting to see this study repeated in indi-viduals with depression or a history of depression.

Most studies in humans extrapolate changes inplasma tryptophan to changes in brain levels andvery few studies assess CSF levels of serotonin ortryptophan. The validity of CSF serotonin levels asan index of changes in brain serotonin has alsobeen questioned, with neuroimaging (using radioli-gands) offered as a more sensitive method of assess-ing serotonin metabolism in the brain (29). Salomonet al. (30) measured CSF levels of tryptophan and5-hydroxyindoleacetic acid (5-HIAA), a metaboliteof tryptophan, during tryptophan depletion in individ-uals being treated with sertraline or bupropion. Tryp-tophan depletion elicited a relapse in mood in thosewhose CSF tryptophan fell below 40 nM and deple-tion led to a significant decrease in CSF tryptophanand 5-HIAA and in plasma tryptophan. There wasa strong and significant inverse correlation betweenmood and CSF tryptophan levels during tryptophandepletion, but mood did not correlate significantlywith CSF 5-HIAA or plasma-free tryptophan levels.The association between plasma and CSF levels wasnot consistent: at baseline and before commencingsertraline or bupropion, there was a significant andstrong correlation between CSF and free plasma tryp-tophan, but no significant correlation between CSFtryptophan and 5-HIAA. Following 5 weeks of med-ication, both correlations were not significant. Theresearchers acknowledge that their sample size wassmall (n = 12), making it inappropriate to draw gen-eralisations (30), and this also reflects the difficultiesof recruiting participants for a study with such ademanding protocol.

Tryptophan, mood and the popular press

Much of the scientific research into tryptophan andmood has focused on elucidating mechanisms formood disturbances, rather than trialling tryptophanmanipulation as a clinical treatment. A complicat-ing factor in the interpretation of these studies is thatnot all controlled the composition of the participants’background or baseline diets. The effects of low-ering tryptophan levels may not be purely becauseof serotonin metabolism and may also be medi-ated through other neurotransmitter pathways (31).Further, as tryptophan depletion induces or wors-ens depressive symptoms only in certain groups,depression may not be mediated solely by reducedserotonin (32). In addition, a large epidemiologicalstudy of 29 133 men found no association between

dietary tryptophan intake and self-reported depressedmood, hospital admission for depressive disorders orsuicide (33). In contrast, articles in the lay mediaemphasise ‘treating’ mood through altering trypto-phan levels and thus serotonin levels.

A pure carbohydrate load in fasting individ-uals will significantly increase the plasma tryp-tophan:LNAA ratio compared with placebo (34).Despite scientific commentary and empirical researchshowing the impracticality of using the Wurtmaneffect to alter tryptophan and serotonin levels, theWurtman effect is constantly invoked by the generalmedia. Implementing the Wurtman effect in practiceis problematic. Benton and Donohoe (3) state that amere 5% of calories as protein is sufficient to curb theincrease in the tryptophan:LNAA ratio and that even‘high-carbohydrate’ foods typically still contain suf-ficient protein to prevent this increase. Young (6) putthe protein threshold at 4% of total energy. Bentonand Donohoe (3) note that there is a clear increasein the plasma tryptophan:LNAA ratio when the mealcontains less than 2% of its calories as protein, butthere is little evidence that carbohydrate specificallybenefits depressed individuals.

General media reports regarding the effects oftryptophan are often hyperbolic, misleading andambiguous, with much of their advice and informa-tion being inconsistent with Wurtman’s hypothesisand even basic biochemistry. The list of ‘tryptophan-rich foods’ extolled by lay publications is wide-ranging and includes bananas, turkey, chocolate,dates, papaya, poultry, milk, oats, various nuts andbeans, chickpeas, sunflower seeds, dairy foods, avo-cado, eggs, red meat, soybeans and soy foods, tuna,shellfish, brown rice, lentils, lobster, seafood, whole-grains, hummus, pineapple, asparagus, beetroot andchicken soup (33–52). Protein-rich foods such asmeat, poultry, dairy products, nuts, beans and eggscontain tryptophan (Table 1), but tryptophan is thelimiting amino acid in most protein sources (1,3,6),meaning that it is the essential amino acid which ispresent in the lowest quantity in that food source. Ascan be seen in Table 1, fruits and vegetables are gen-erally poor protein sources, including those recom-mended by the general media, and cannot be viewedas concentrated sources of tryptophan. Another con-sideration is that even if a food is high in proteinand therefore high in tryptophan, it may not be nor-mally eaten in sufficient quantities or frequency tobe a significant dietary source.

While a few lay articles provide sound andscientific information (54–56), many reports areambiguous or misleading. Carbohydrate foods arealso recommended to increase serotonin levels,although the way these foods do this is not alwaysexplained (45,50). Recommending milk as a source

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Table 1. Total protein and tryptophan levels in various ‘tryptophan-rich foods’commonly cited by the general media

Food

Protein(g/100 g edible

portion)

Tryptophan(mg/100 g

edible portion)

Asparagus (boiled)∗ 2.9Avocado 2.0 26Bananas 1.7 28Beans (baked, canned) 4.6 66Beetroot (canned, drained) 1.3 9Brown rice 2.9 38Cashew nuts (roasted) 16.7 319Cheese (cheddar) 25.9 357Chicken breast (baked, lean) 29.0 394Chickpeas (canned, drained)∗ 6.3Cream of chicken soup (canned, reconstituted)∗ 1.8Dates (dried)∗ 2.0Eggs (hard boiled) 13.0 209Hazelnuts (raw)∗ 14.8King prawns (cooked) 23.7 178Lamb leg (roasted, lean) 29.7 400Lentils (boiled) 6.8 49Lobster (steamed or boiled)∗ 22.0Milk (full cream) 3.3 42Milk chocolate 8.2 112Oats (rolled, boiled as porridge) 2.0 25Pawpaw (papaya)∗ 0.4Peanuts (roasted) 25.1 285Pineapple (raw, peeled)∗ 0.6Soy beverage (regular fat, unflavoured, unfortified) 2.6 39Soybeans (boiled) 13.5 203Sunflower seeds 22.7 347Tofu (soft)∗ 8.9Tuna (canned in brine, drained) 23.8 208Turkey breast (baked, lean) 29.4 372Wholemeal bread 8.8 112

Source: NUTTAB 2006 (53).∗Tryptophan levels were not available for these foods but their protein contents arelisted here for readers’ interest (53).

of both protein (and thus tryptophan) and carbohy-drate to increase serotonin (57) shows a lack ofunderstanding of the mechanism behind the Wurt-man effect. One magazine article went so far asto say ‘brains can only make serotonin when weeat starchy carbs. . .without protein’, only to thenadd ‘The more tryptophan you eat with carbo-hydrates, the cheerier you become. . . Tryptophanis enhanced with carbohydrates, so the key is toeat something that contains tryptophan with com-plex carbohydrates. . .’ (58). Unfortunately, the arti-cle did not explain how eating tryptophan couldbe achieved without eating protein in the dailydiet. Some newspaper columnists advise eating pro-tein and carbohydrate foods separately (59) or toeat low-protein-high-carbohydrate meals to improvemood (60), but neglect to explain that a protein foodcontains tryptophan along with other amino acids andthat ‘carbohydrate foods’ such as bread also contain

protein. In the case of white bread, protein formsabout 14% of its caloric content. General mediaarticles also show a lack of understanding in bio-chemistry, in that tryptophan, as an amino acid, isa component of protein; they describe proteins asstimulatory and tryptophan as calming (61). Somepublished statements are profoundly misleading, suchas ‘. . .tryptophan, which is plentiful in carbohydrate-rich foods, such as chocolate’ (62) and ‘starch- andsugar-rich breakfast cereals. . .are high in the aminoacid tryptophan. . .’ (63). Tryptophan is an aminoacid, not a carbohydrate, and although chocolatedoes contain an appreciable amount of protein alongwith fat and carbohydrate, the protein content wouldreduce rather than increase brain uptake of trypto-phan (3). As described in the studies reviewed above,the whey protein α-lactalbumin is rich in tryptophanbut needs to be consumed as a supplement and notas an intact food and thus is still an artificial methodfor influencing plasma tryptophan levels. Lastly, pub-lished personal testimonials detailing success in treat-ing depression by dietary manipulation often do notreport what the pre-existing diet was like (35,64).

Toxicity, side-effects and caveats

The outbreak of eosinophilia-myalgia syndrome(EMS) in 1989 in individuals using over-the-counterl-tryptophan supplements resulted in these supple-ments being banned in the United States (65,66).EMS is characterised by elevated blood eosinophilcount, myalgia and sometimes neurological and pul-monary complications (65,66). The syndrome wasthought to be caused by contaminants, although itcould not be convincingly established whether thesecompounds were responsible (65).

Supplementation with tryptophan as an amino acidcan have side-effects, including nausea, vomiting,headaches and drowsiness (67); such side-effectsalso occur with consuming amino acid loads intryptophan depletion studies (12,23). A 6 g oral loadof tryptophan in healthy adults significantly increasedlipid peroxidation and tryptophan metabolites ofthe kynureinine pathway after 5 and 7 h comparedwith baseline. This potentially promotes cellularoxidative stress, damage or death, which may haveclinical implications in individuals either takingtryptophan supplements or following popular high-protein diets (68).

Mood changes may not occur until plasma tryp-tophan has dropped below a certain level, anda 60% decrease has been suggested as a thresh-old (31). Also, individuals with a family or per-sonal history of depression or who are chronicallystressed may be more sensitive to tryptophan changesinduced through dietary means (19,23), while healthy

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young individuals may be less susceptible (16,19).Robinson and Sahakian (69) found that in healthywomen, depletion of plasma tryptophan in itselfwas not associated with negative mood. However,when negative mood was induced during tryptophandepletion, this was associated with more pronouncednegative mood on a subsequent episode of trypto-phan depletion. Thus, individuals with concurrentdepressed mood and reduced serotonin may be sen-sitive to changes in tryptophan levels.

Conclusion

Research into tryptophan must continue to elucidateits role in mood and mood disorders, and in themechanisms behind SSRNIs. Most of the studies todate have been on small to modest sample sizes,and hence more studies with larger sample sizes areneeded, along with studies in individuals with currentdepression. Empirical studies have mostly shownthat healthy individuals are insensitive to changesin tryptophan levels and for those who do have apersonal or family history of depression, the resultsare inconsistent.

It is unlikely that the highly artificial dietaryregimens used in studies such as Markus et al. (8)would be popular in the community and sustainedfor any length of time, if diet alone were usedto alter brain serotonin levels. As Benton andDonohoe (3) state, ‘No normal meal will contain solittle protein that the uptake of tryptophan will beincreased’ (p404). However, many general mediaarticles give contradictory and impractical advice.The articles convey the impression that mood can beimproved with ‘tryptophan-rich foods’ or by eatingcarbohydrate to raise serotonin levels, but do notconsider whether this would be of any use to thosewithout depression. It is questionable whether dietarychanges to manipulate tryptophan levels, even ifachievable, would be of advantage to the generalpopulation. This does not detract from the importanceof a nutritious diet for individuals with depression,as well as the general population, for overall health.

Acknowledgement

Over the past 48 months, Nerissa Soh and Garry Walter have hadno competing interests.

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